Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling for Iron-Regulated Hematopoietic Stem and Progenitor Cells’ Commitment toward Erythroid and Megakaryocytic Lineages

Iron replenishment is a cornerstone therapy for anemia in diverse diseases. While its role in erythrocyte hemoglobinization is well-established, the broader impact of iron on other aspects of hematopoiesis, such as thrombopoiesis, remains poorly understood. In this study, we demonstrate that iron plays a regulatory role in the commitment of hematopoietic stem and progenitor cells (HSPCs) toward erythroid and megakaryocytic lineages. Using colony-forming unit assays and flow cytometry, we observed that iron increases the proportion of erythroid cells while reducing the proportion of megakaryocytic cells. Transcriptomic profiling and functional output analyses identified the MAPK/ERK pathway as a critical mediator of iron-regulated HSPCs' commitment. Corroborating <i>in vitro</i> findings, rats with iron deficiency anemia exhibited continuously elevated platelets and decreased red blood cell counts, while intravenous iron supplementation reversed these effects. This effect of iron was enhanced in combination with erythropoietin, a key cytokine in erythropoiesis. A mechanism-based pharmacokinetic/pharmacodynamic model was developed to quantify the impact of iron on the two lineages. The dynamic interplay between iron levels and the development of erythropoiesis and thrombopoiesis was accurately recapitulated in rats. The model was further extrapolated to humans and validated with clinical data. Overall, this work not only provides functional insights into the pivotal role of iron in erythropoiesis and thrombopoiesis but also holds translational implications for optimizing iron therapy in anemia and potentially other hematologic conditions where erythropoiesis and thrombopoiesis are affected.